Wang et al. Cell Biosci (2020) 10:147 https://doi.org/10.1186/s13578-020-00512-1 Cell & Bioscience

REVIEW Open Access Explore a novel function of human condensins in cellular senescence Hongzhen Wang1,2* , Xin Liu1 and Guiying Li2

Abstract There are two kinds of condensins in human cells, known as condensin I and condensin II. The canonical roles of condensins are participated in chromosome dynamics, including chromosome condensation and segregation during cell division. Recently, a novel function of human condensins has been found with increasing evidences that they play important roles in cellular senescence. This paper reviewed the research progress of human condensins involved in diferent types of cellular senescence, mainly oncogene-induced senescence (OIS) and replicative senescence (RS). The future perspectives of human condensins involved in cellular senescence are also discussed. Keywords: Human condensins, Cellular senescence, Oncogene-induced senescence, Replicative senescence

Introduction Although both human condensins have similar com- Condensins were frstly identifed for their fundamen- ponents and alphabetic structure, they show diferent tal roles in establishment and maintenance of mitotic nuclear distribution, localization on chromosomes and chromosome condensation in cell-free system from play distinct roles in chromosome dynamics during mito- Xenopus laevis eggs [1, 2]. Until now, most multicellu- sis [9–13]. lar eukaryotes reported have two kinds of condensins, In detail, during interphase condensin I is present in termed as condensin I and condensin II [3–6]. Te two the cytoplasm, whereas condensin II is enriched within kinds of condensins are also exist in human cells [7–10]. the nucleus [10, 14, 15]. During mitosis, initially conden- Both human condensins are pentameric complexes com- sin II participates in chromosome condensation within posed of shared core SMC2/SMC4 (structural mainte- the nucleus in early prophase, whereas condensin I can nance of chromosomes, SMC) heterodimer(also known interact with chromosomes only after the nuclear enve- as hCAP-E/hCAP-C)and three accessory non-SMC lope breaks down [11]. Human condensin I shows a subunits, including a kleisin subunit and two HEAT- two-step dynamic binding. Once nuclear envelope break- repeat proteins. Tey are hCAP-H(NCAPH), hCAP- down, human condensin I rapidly associated with mitotic D2(NCAP-D2) and hCAP-G(NCAPG) for condensin chromosomes then remained constant from prometa- I and hCAP-H2(NCAP-H2), hCAP-D3(NCAPD3) and phase to late metaphase and chromatin bound human hCAP-G2(NCAP-G2) for condensin II [10–12]. condensin I increased again just from anaphase onset Te canonical roles of human condensins are partici- until late anaphase when it dissociated from chromo- pated in chromosome dynamics, including chromosome somes[11, 12]. Similarly, human condensin I complexes condensation and segregation during mitosis [7–12]. dynamically bind to chromosomes in two steps during prometaphase and early anaphase whereas human con- densin II complexes are stably bound to chromosomes *Correspondence: [email protected] throughout mitosis. Localization of human condensin II 2 Key Laboratory for Molecular Enzymology and Engineering is centrally confned, but condensin I reaches 50% of of the Ministry of Education, School of Life Sciences, Jilin University, ∼ 130012 Changchun, People’s Republic of China the chromatid diameter from its center [16]. It is indi- Full list of author information is available at the end of the article cated that human condensin II but not condensin I is

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco​ ​ mmons.org/licen​ ses/by/4.0/​ . The Creative Commons Public Domain Dedication waiver (http://creativeco​ mmons​ .org/publi​ cdoma​ in/​ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Cell Biosci (2020) 10:147 Page 2 of 7

more indispensible for the salt-dependent, reversible condensed state of the nucleus, homologous recombina- reorganization of condensin II-based axes in chromo- tion repair and gene expression during interphase [20, some shaping [17]. Moreover, human condensins show 24–35]. Beyond the multiple roles of human condensins a discontinuous pattern along mitotic chromosomes mentioned above, increasing evidences show a novel and play a major role in controlling the elastic stifness function of human condensins in cellular senescence [36, of metaphase chromosomes. Depletion of condensin II 37]. impacts chromosome mechanics more than depletion Cellular senescence plays important protective roles in of condensin I and stifness of the metaphase chromo- development, tissue homeostasis, wound healing, mul- some is more dependent on condensin II than on con- tiple age-related diseases and cancer [38, 39]. Cellular densin I [18].Tis idea is somewhat inconsistent with a senescence is a stable state of irreversible cell cycle arrest former study. It has been demonstrated that human con- caused by various forms of cellular stresses. Senescent densin I but not condensin II can associate with KIF4A cells lose DNA replication ability and still maintain cel- to confer rigidity to centromeres [19]. During anaphase, lular metabolic activity [40, 41]. Especially, cellular senes- when human condensins are depleted, chromosomes are cence can also be induced by pathophysiological stimuli, formed with improperly structured kinetochores and such as ROS (reactive oxygen species), oncogene acti- chromosome bridges appear in the cell [20]. Likewise, vation, cytotoxic drugs and aging [38]. Nowadays four when human condensins are knocked down or dysfunc- kinds of cellular senescence are recognized, i.e., onco- tion in human cells, chromatin bridges between daugh- gene-induced senescence (OIS), replicative senescence ter cells in anaphase and multiple nuclei in single cells are (RS), stress-induced premature senescence (SIPS) and observed[21, 22]. During telophase, human condensins therapy-induced senescence (TIS) [37, 38, 41, 42]. OIS are involved in the mitotic chromosome conformation is induced by oncogene expression and RS is induced by transformation into the interphase state as well. Recently, telomere shortening [37, 38, 41, 43–45]. SIPS is induced it is identifed telophase as a critical transition between by various external signals, such as UV, hyperoxia, hydro- condensin- and cohesin-driven chromosome folding gen peroxide, etc. [41, 45]. TIS is caused by traditional [23]. Consistently, human condensin II can initiate sis- cancer therapy and it can be an efective way to treat can- ter chromatid resolution during S phase [24]. Altogether, cer while lessening side efects [42, 46–48]. the diferences in the timing of binding to chromosome Although human condensins play classical roles in and mutant phenotypes of dysfunction strongly indicated chromosome dynamics during mitosis, their nonmitotic that human condensin I and II have fundamentally dis- functions have been payed more and more attention than tinct functions during mitosis. Diferent nuclear distribu- before. As a novel function of human condensins in cel- tion, localization on chromosomesof human condensin I lular senescence during interphase, much more problems and human condenisn II during cell cycle are shown as remain to be further explored. Tis paper reviewed the Fig. 1. research progress of human condensins involved in dif- In addition to their mitotic functions, human con- ferent types of cellular senescence, mainly oncogene- densins also play important roles in the prestressed induced senescence (OIS) and replicative senescence

Fig. 1 Diferent nuclear distribution, localization on chromosomes of human condensin I and condensin II during cell cycle (one chromosome is illustrated as an example) Wang et al. Cell Biosci (2020) 10:147 Page 3 of 7

(RS). Te future perspectives of human condensins in the upregulation of senescence genes upon senescence. cellular senescence are also discussed. Terefore, the roles of human condensin II in cellular senescence may be through compartmental reorganiza- Human condensins involved in cellular senescence tions coupled to gene regulation [37]. Firstly, human condensins are involved in OIS. Initially, Secondly, human condensins are involved in RS. SMC2 human condensin II is found to play a novel role in OIS. and SMC4, core subunits of human condensins, are dem- Overexpression of human condensin II, but not human onstrated to be down-regulated in the serially passaged condensin I, induces cellular senescence and senescence- fbroblast cells by proteomic study and they are sup- associated heterochromatic foci (SAHF) formation and posed to play an important role in RS [41]. Consistently, depletion of human condensin II inhibits the establish- several subunits of human condensin I and II (mainly ment of OIS [36]. In detail, the N-terminus truncated non-SMC subunits, i.e., hCAP-D2, hCAP-D3, hCAP- variant, hCAP-H2ΔN (lacking the frst 50 amino acids) is G, hCAP-G2, hCAP-H and SMC4) are downregulated mostly localized at the nuclear matrix and accumulates in in KDM3A- or KDM4C-knockdown human umbilical quiescent and senescent cells. Te ΔN variant exists as an cord-derived stromal cells (hUCMSCs) or upregulated insoluble nuclear structure while the full-length hCAP- in KDM3A or KDM4C-overexpressing hUCMSCs (49). H2 associates with mitotic chromosome. Overexpression Especially, hCAPD-2 and hCAPG-2 are positively regu- of the full-length hCAP-H2 and ΔN variant can signif- lated by KDM3A and KDM4C with their H3K9 demethy- cantly induce senescence. Expression of hCAP-H2ΔN lase activity and human condensins regulated by KDM3A was increased during OIS. Moreover, hCAP-H2 knock- or KDM4 might be critical for stability of the heterochro- down (KD) also inhibited Ras-induced senescence. It is matin structure during senescence. Recently,as men- suggested that human condensin II drives senescence via tioned above, human condensin II is involved in BA and nuclear/genomic reorganization [36]. Recently, the roles AB transitions not only during OIS but also during RS of human condensin II are reported to participate in cel- [37]. lular senescence through compartmental reorganiza- Hitherto, there are few literatures published from tions coupled to gene regulation [37]. Human condensins the point that human condensins are involved in strengthen and expand euchromatic A compartments stress-induced premature senescence (SIPS) and ther- and promote/maintain BA transitions upon senescence. apy-induced senescence (TIS) [36, 37, 49]. Abnormal Concretely, localization of hCAP-H2 is frstly studied and expression of subunits of human condensins and changes the results show they localize at active senescence genes, of structure of chromosomes in four types of cellular highly transcribed housekeeping genes, and potential senescence are shown in Table 1. enhancers. Next, by compared the general organization of the human genome into A and B compartments in OIS Conclusions and growing cells, it is found that A compartments in Apart from the multiple canonical functions of chro- OIS cells were signifcantly enlarged (~ 50%) compared to mosome dynamics played by human condensins dur- counterparts in growing cells. Te increased BA transi- ing mitosis and interphase, increasing evidences show tions result in the signifcant enlargement of A compart- a novel function of human condensins in cellular senes- ments in OIS cells compared to growing cells. In eforts cence. Human condensins play important roles in the to fnd a functional link between senescence-dependent main two types of cellular senescence, i.e. oncogene- compartmental reorganizations and condensin, the fol- induced senescence (OIS) and replicative senescence lowing results show that human condensin II binding (RS). and dissociation are involved in BA and AB transitions and this mechanism is conserved between OIS and RS. Future perspectives of human condensins in cellular In addition to promoting and maintaining BA transi- senescence tions, human condensin II also play important roles to To explore a novel function of human condensins in cel- maintain euchromatic A compartments and facilitate lular senescence, three future perspectives are presented genomic contacts in A compartments, that is, to rein- as follows. force A compartments. Further research suggests that Firstly, how human condensins involved in inter- human condensin II plays a direct role in the upregula- phase nuclear reorganization during cellular senescence tion of senescence genes because that many genes upreg- needs further study. Both human condensin I and II are ulated upon OIS and downregulated by hCAP-H2 KD required for maintenance of the interphase nuclear archi- (knock down) are hCAP-H2 binding genes. Collectively, tecture. Human condensins regulated by KDM3A or human condensins are not only involved in euchromatic KDM4 might be critical for stability of the heterochroma- A compartments and BA transitions, but also involved in tin structure during senescence [49]. Depletion of human Wang et al. Cell Biosci (2020) 10:147 Page 4 of 7

Table 1 Abnormal expression of subunits of human condensins and changes of structure of chromosomes in four types of cellular senescence Types of cellular Abnormal expression of subunits Changes of structure of chromosomes Number of literature senescence of human condensins

OIS hCAPH2 Formation of senescence-associated heterochro- [36, 37, 41 (Supplementary hCAPH2ΔN↑ matic foci (SAHF), drives senescence via nuclear/ Fig. 8)] SMC2 , SMC4↑ genomic reorganization; strengthen and expand ↓ ↓ euchromatic A compartments and promote/main- tain BA transitions upon senescence RS SMC2 SAHF were not detected in RS cells, the sizes of [37, 41, 43–45, 49 (Supple- SMC4↓ both A and B compartments became signifcantly mentary Figure S4)] hCAP-D2(NCAPD2)↓ enlarged and the numbers of A and B compart- hCAP-D3(NCAPD3)↓ ments decreased; heterochromatin reorganization hCAP-G(NCAPG) ↓ to restrain DNA damage and progression of MSC hCAP-G2(NCAPG2)↓ senescence via transcriptionally activating human hCAP-H()(NCAPH) ↓, hCAPH2((NCAPH2) condensins; telomere shortening ↑ ↑ SIPS Unpublished [37, 41, 49] TIS Unpublished [37, 41, 49]

“ ” is a symbol as upregulation of expression, “ ” is a symbol as downregulation of expression ↑ ↓ condensin II leads to dramatic disruption of nuclear silencing and dramatic chromatin condensation through architecture and nuclear size [50]. Interaction between binding throughout the budding yeast genome and human condensin II and SAHF provide an additional induces the formation of large chromatin loop domains platform for studies on condensins participating dynamic [62]. Hitherto, apart from cellular senescence and tumor- interphase chromatin reorganization [51]. Recently, genensis, whether human condensins play a role in qui- human condensin II subunit hCAP-H2 is demonstrated escence is unclear. In addition, how human condensins to associate with shelterin protein TRF1 and be required involved the three processes need be extensively explored for telomere stability [52]. Furthermore, there is small [41, 49, 52, 62]. It is promising to explore possible inter- fraction of human condensin I retained and be active in plays of cellular senescence and tumor formation and both gene regulation and chromosome condensation in anticancer therapy from the viewpoints of human con- interphase nuclei [53–55]. Although human condensin densins [63–65]. II is reported to be involved in SAHF formation and BA Finally, whether some crosstalks exist in condensins, and AB transitions, whether human condensin I involved cohesins and SMC5/SMC6 complexes is yet unclear these process is still unclear [36, 37]. It is also intriguing during human cellular senescence. SMC complexes to explore what roles of human condensin I play in cellu- have ancient origins and share structural similari- lar senescence during interphase. ties. Condensin, cohesin and SMC5/SMC6 complex Secondly, the diferent functions and possible inter- are three types of evolutionarily conserved SMC com- plays of human condensins in cellular senescence, quies- plexes within eukaryotic cells and the three complexes cence and carcinogenesis needs further study. Although are all reported to be involved in cellular senescence cell cycle diferences exist between cellular senescence in diferent organisms. Concretely, loss of the recruit- and quiescence, either cellular senescence or quiescence ment cohesin and condensin I complexes to pericen- misregulation is implicated in cancer progression [39, 42, tromeric regions causes to block efcient repair of 56, 57]. It is surprising that condensins are involved in all the regions and leads to formation of persistent DNA the three processes [36, 37, 41, 49, 58–62]. In a mutant damage foci in senescent human adult stem cells [66]. mouse carrying a constitutive missense mutation in Depletion of human SMC5/6 subunits by RNAi inhib- the condensin II kleisin-β subunit Caph2, the mutation its telomere homologous recombination and causing specifcally causes chromatin decondensation and con- telomere shortening and cellular senescence in human densin II is demonstrated to be required for peripheral ALT (ALT, alternative lengthening of telomeres) cells T-cell development and maintenance of the quiescent [67, 68]. Similarly, SMC5/SMC6 complex as a target of state [58–60]. With further analysis, the mutant mice Mms21-dependent sumoylation is also involved in cel- show condensin II-dependent thymic lymphomas for- lular senescence in Saccharomyces cerevisiae [69]. Of mation through tissue-specifc genome instability [61]. note, interaction of condensin and cohesin is reported Recently, in the quiescent state of Saccharomyces cerevi- as a chromosome folding intermediate during telo- siae, condensin is required for widespread transcriptional phase as a critical transition between condensin- and Wang et al. Cell Biosci (2020) 10:147 Page 5 of 7

cohesin-driven chromosome folding [23]. Distinct roles Received: 5 July 2020 Accepted: 6 December 2020 of cohesin and condensin are required in the estab- lishment of 3D nuclear organization in Drosophila [70]. Common kleisin-hinge interaction and diferent References modes of regulation are also proposed in condensin 1 Hirano T, Mitchison TJ. A heterodimeric coiled-coil protein required for and cohesin in fssion yeast [71]. Likewise, functional mitotic chromosome condensation in vitro. Cell. 1994;79:449–58. https​:// interplay between cohesin and Smc5/6 complexes is doi.org/10.1016/0092-8674(94)90254​-2. 2 Hirano T, Kobayashi R, Hirano M. Condensins chromosome condensation reviewed for signifcant overlap of their location, func- protein complexes containing XCAP-C, XCAP-E and a Xenopus homolog tion and crosstalk between these two complexes [72]. of the Drosophila barren protein. Cell. 1997;89:511–21. https​://doi. Similarly, there are also papers about interactions with org/10.1016/s0092​-8674(00)80233​-0. 3 Lišková L, Šušor A, Pivoňková K, Sasková A, Karabínová P, Kubelka M. condensin and Smc5/6 complexes. Depletion of Smc5 Detection of condensin I and II in maturing pig oocytes. Rep Fertil Dev. and Smc6 results in abnormal distribution of con- 2010;22:644–52. https​://doi.org/10.1071/RD090​68. densins and chromosome segregation errors in human 4 Lee J, Ogushi S, Saitou M, Hirano T. Condensins I and II are essential for construction of bivalent chromosomes in mouse oocytes. Mol Biol Cell. cells [73]. Furthermore, mutation of SMC5 also leads 2011;22:3465–77. https​://doi.org/10.1091/mbc.E11-05-0423. to abnormal distribution of condensin along chro- 5 Fujiwara T, Tanaka K, Kuroiwa T, Hirano T. Spatiotemporal dynamics of mosomes with decreased condensin accumulation at condensins I and II: evolutionary insights from the primitive red alga Cyanidioschyzon merolae. Mol Biol Cell. 2013;24:2515–27. https​://doi. pericentromeric regions and enrichment of condensin org/10.1091/mbc.E13-04-0208. on chromosome arms in mouse embryonic stem cells 6 Sakamoto T, Sugiyama T, Yamashita T, Matsunaga S. Plant condensin II is (mESCs) [74]. Tere are complex chromatin reorgani- required for the correct spatial relationship between centromeres and rDNA arrays. Nucleus. 2019;10:116–25. https​://doi.org/10.1080/19491​ zations in senescent cells [75–77]. Recently, diferent 034.2019.16165​07. models of SMC complex function have been presented 7. Schmiesing JA, Gregson HC, Zhou S, Yokomori K. A human condensin [78–80]. Based on all mentioned above, we propose complex containing hCAP-C-hCAP-E and CNAP1, a homolog of Xenopus XCAP-D2, colocalizes with phosphorylated histone H3 during the early that senescence-associated chromatin reorganization stage of mitotic chromosome condensation. Mol Cell Biol. 2000;20:6996– may need cooperative function of the three SMC com- 7006. https​://doi.org/10.1128/mcb.20.18.6996-7006.2000. plexes, but the molecular mechanism is yet unknown. 8. Yeong FM, Hombauer H, Wendt KS, Hirota T, Mudrak I, Mechtler K, Loreg- ger T, Marchler-Bauer A, Tanaka K, Peters JM, Ogris E. Identifcation of a Taken together, human condensins play important subunit of a novel Kleisin-beta/SMC complex as a potential substrate roles in cellular senescence. It is worthy to be explored of protein phosphatase 2A. Curr Biol. 2003;13:2058–64. https​://doi. for the new multifunctions of human condensins in cel- org/10.1016/j.cub.2003.10.032. 9. Kimura K, Cuvier O, Hirano T. Chromosome condensation by a lular senescence. human condensin complex in Xenopus egg extracts. J Biol Chem. Acknowledgements 2001;276:5417–20. https​://doi.org/10.1074/jbc.C0008​73200​. Not applicable. 10. Ono T, Losada A, Hirano M, Myers MP, Neuwald AF, Hirano T. Diferential contributions of condensin I and condensin II to mitotic chromosome Authors’ contributions architecture in vertebrate cells. Cell. 2003;115:109–21. https​://doi. HZW wrote the manuscript. XL collected some references and revised the org/10.1016/s0092​-8674(03)00724​-4. manuscript, GYL revised the manuscript. All authors read and approved the 11. Ono T, Fang Y, Spector DL, HiranoT. Spatial and temporal regulation of fnal manuscript. condensins I and II in mitotic chromosome assembly in human cells. Mol Biol Cell. 2004;15:3296–308. https​://doi.org/10.1091/mbc.e04-03-0242. Funding 12 Hirota T, Gerlich D, Koch B, Ellenberg J, Peters JM. Distinct functions Funding from the National Natural Science Foundation of China (31,570,934) of condensin I and II in mitotic chromosome assembly. J Cell Sci. and from Foundation of Jilin Educational Committee (project No. 2004;117:6435–45. https​://doi.org/10.1242/jcs.01604​. JJKH20170380KJ). 13. Onn I, Aono N, Hirano M, Hirano T. Reconstitution and subunit geometry of human condensin complexes. EMBO J. 2007;26:1024–34. https​://doi. Availability of data and materials org/10.1038/sj.emboj​.76015​62. Not applicable. 14. Gerlich D, Hirota T, Koch B, Peters JM, Ellenberg J. Condensin I stabilizes chromosomes mechanically through a dynamic interaction in live cells. Ethics approval and consent to participate Curr Biol. 2006;16:333–44. https​://doi.org/10.1016/j.cub.2005.12.040. Not applicable. 15 Hirano T. Condensin-based chromosome organization from bacte- ria to vertebrates. Cell. 2016;164:847–57. https​://doi.org/10.1016/j. Consent for publication cell.2016.01.033. All authors read and approved the fnal manuscript for publication. 16 Walther N, Hossain MJ, Politi AZ, Koch B, Kueblbeck M, Ødegård-Fougner Ø, Lampe M, Ellenberg J. A quantitative map of human Condensins Competing interests provides new insights into mitotic chromosome architecture. J Cell Biol. The authors declare that they have no competing interests. 2018;217:2309–28. https​://doi.org/10.1083/jcb.20180​1048. 17 Ono T, Sakamoto C, Nakao M, Saitoh N, Hirano T. Condensin II plays an Author details essential role in reversible assembly of mitotic chromosomes in situ. Mol 1 School of Life Sciences, Jilin Normal University, 136000 Siping, People’s Biol Cell. 2017;28:2875–86. https​://doi.org/10.1091/mbc.E17-04-0252. Republic of China. 2 Key Laboratory for Molecular Enzymology and Engi- 18. Sun M, Biggs R, Hornick J, Marko JF. Condensin controls mitotic chromo- neering of the Ministry of Education, School of Life Sciences, Jilin University, some stifness and stability without forming a structurally contiguous 130012 Changchun, People’s Republic of China. scafold. Chromosome Res. 2018;26:277–95. https​://doi.org/10.1007/ s1057​7-018-9584-1. Wang et al. Cell Biosci (2020) 10:147 Page 6 of 7

19 Takahashi M, Wakai T, Hirota T. Condensin I-mediated mitotic chromo- 38 Parry AJ, Narita M. Old cells, new tricks: chromatin structure in senes- some assembly requires association with chromokinesin KIF4A. Genes cence. Mamm Genome. 2016;27:320–31. https​://doi.org/10.1007/s0033​ Dev. 2016;30:1931–6. https​://doi.org/10.1101/gad.28285​5.116. 5-016-9628-9. 20. Samoshkin A, Arnaoutov A, Jansen LE, Ouspenski I, Dye L, Karpova T, 39. Kim YH, Park TJ. (2019) Cellular senescence in cancer. BMB Rep 52:42–6. McNally J, Dasso M, Cleveland DW, Strunnikov A. Human condensin https​://doi.org/10.5483/BMBRe​p.2019.52.1.295. function is essential for centromeric chromatin assembly and proper 40. Salama R, Sadaie M, Hoare M, Narita M. (2014) Cellular senescence and sister kinetochore orientation. PLoS ONE. 2009;4(8):e6831. https​://doi. its efector programs. Genes Dev 28:99–114. https​://doi.org/10.1101/ org/10.1371/journ​al.pone.00068​31. gad.23518​4.113. 21. Zhai L, Wang HZ, Tang W, Liu WG, Hao S, Zeng XL. Disturbance in function 41. Meng Q, Gao J, Zhu H, He H, Lu Z, Hong M, Zhou H. (2018) The proteomic and expression of condensin afects chromosome compaction in HeLa study of serially passaged human skin fbroblast cells uncovers down- cells. Cell Biol Int. 2011;35:735–40. https​://doi.org/10.1042/CBI20​10064​6. regulation of the chromosome condensin complex proteins involved 22. Samoshkin A, Dulev S, Loukinov D, Rosenfeld JA, Strunnikov AV. Con- in replicative senescence. Biochem Biophys Res Commun 505:1112–20. densin dysfunction in human cells induces nonrandom chromosomal https​://doi.org/10.1016/j.bbrc.2018.10.065. breaks in anaphase, with distinct patterns for both unique and repeated 42. Lee S, Lee JS. Cellular senescence: a promising strategy for cancer genomic regions. Chromosoma. 2012;121:191–9. https​://doi.org/10.1007/ therapy. BMB Rep. 2019;52:35–41. https​://doi.org/10.5483/BMBRe​ s0041​2-011-0353-6. p.2019.52.1.294. 23. Abramo K, Valton AL, Venev SV, Ozadam H, Fox AN, Dekker J. A chromo- 43. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras some folding intermediate at the condensin-to-cohesin transition during provokes premature cell senescence associated with accumulation of telophase. Nat Cell Biol. 2019;21:1393–402. https​://doi.org/10.1038/s4155​ p53 and p16INK4a. Cell. 1997;88:593–602. https​://doi.org/10.1016/s0092​ 6-019-0406-2. -8674(00)81902​-9. 24. Ono T, Yamashita D, Hirano T. Condensin II initiates sister chromatid 44. Gorgoulis VG, Halazonetis TD. Oncogene-induced senescence: the bright resolution during S phase. J Cell Biol. 2013;200:429–41. https​://doi. and dark side of the response. Curr Opin Cell Biol. 2010;22:816–27. https​ org/10.1083/jcb.20120​8008. ://doi.org/10.1016/j.ceb.2010.07.013. 25. Takemoto A, Kimura K, Yanagisawa J, Yokoyama S, Hanaoka F. Negative 45. de Magalhães JP, Passos JF. Stress, cell senescence and organismal regulation of condensin I by CK2-mediated phosphorylation. EMBO J. ageing. Mech Ageing Dev. 2018;170:2–9. https​://doi.org/10.1016/j. 2006;25:5339–48. https​://doi.org/10.1038/sj.emboj​.76013​94. mad.2017.07.001. 26. Barnhart-Dailey MC, Trivedi P, Stukenberg PT, Foltz DR. HJURP interaction 46. Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel with the condensin II complex during G1 promotes CENP-A deposition. ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype Mol Biol Cell. 2017;28:54–64. https​://doi.org/10.1091/mbc.E15-12-0843. distinguishes tumor cells that undergo terminal proliferation arrest after 27. Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Grifths PD, Neumann LM, exposure to anticancer agents. Cancer Res. 1999;59:3761–7. Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in micro- 47. Chang BD, Xuan Y, Broude EV, Zhu H, Schott B, Fang J, Roninson IB. Role cephalin cause aberrant regulation of chromosome condensation. Am J of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest Hum Genet. 2004;75:261–6. https​://doi.org/10.1086/42285​5. induced in human tumor cells by chemotherapeutic drugs. Oncogene. 28. Trimborn M, Schindler D, Neitzel H, Hirano T. Misregulated chromosome 1999;18:4808–18. https​://doi.org/10.1038/sj.onc.12030​78. condensation in MCPH1 primary microcephaly is mediated by condensin 48. Bojko A, Czarnecka-Herok J, Charzynska A, Dabrowski M, Sikora E. Diver- II. Cell Cycle. 2006;5:322–6. https​://doi.org/10.4161/cc.5.3.2412. sity of the senescence phenotype of cancer cells treated with chemo- 29. Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1 associates with the therapeutic agents. Cells. 2019;8:1501. https​://doi.org/10.3390/cells​81215​ condensin II complex to function in homologous recombination repair. J 01. Biol Chem. 2008;283:29586–92. https​://doi.org/10.1074/jbc.M8040​80200​. 49. Huang B, Wang B, Yuk-Wai Lee W, Pong UK, Leung KT, Li X, Liu Z, Chen 30. Yamashita D, Shintomi K, Ono T, Gavvovidis I, Schindler D, Neitzel H, R, Lin JC, Tsang LL, Liu B, Ruan YC, Chan HC, Li G, Jiang X. KDM3A and Trimborn M, Hirano T. MCPH1 regulates chromosome condensation KDM4C regulate mesenchymal stromal cell senescence and bone aging and shaping as a composite modulator of condensin II. J Cell Biol. via condensin-mediated heterochromatin reorganization. iScience. 2011;194:841–54. https​://doi.org/10.1083/jcb.20110​6141. 2019;21:375–90. https​://doi.org/10.1016/j.isci.2019.10.041. 31. Heale JT, Ball AR Jr, Schmiesing JA, Kim JS, Kong X, Zhou S, Hudson DF, 50. George CM, Bozler J, Nguyen HQ, Bosco G. (2014) Condensins are Earnshaw WC, Yokomori K. Condensin I interacts with the PARP-1-XRCC1 required for maintenance of nuclear architecture. Cells 3:865–82. https​:// complex and functions in DNA single-strand break repair. Mol Cell. doi.org/10.3390/cells​30308​65. 2006;21:837–48. https​://doi.org/10.1016/j.molce​l.2006.01.036. 51. Ito Y, Narita M. The expanding territories of condensin II. Cell Cycle. 32. Kong X, Stephens J, Ball AR Jr, Heale JT, Newkirk DA, Berns MW, 2015;14:2723–4. https​://doi.org/10.1080/15384​101.2015.10633​56. Yokomori K. Condensin I recruitment to base damage-enriched DNA 52. Wallace HA, Rana V, Nguyen HQ, Bosco G. Condensin II subunit NCAPH2 lesions is modulated by PARP. 1PLoS One. 2011;6(8):e23548. https​://doi. associates with shelterin protein TRF1 and is required for telomere stabil- org/10.1371/journ​al.pone.00235​48. ity. J Cell Physiol. 2019;234:20755–68. https​://doi.org/10.1002/jcp.28681​. 33. Zhang T, Si-Hoe SL, Hudson DF, Surana U. Condensin recruitment to 53. Cabello OA, Eliseeva E, He WG, Youssoufan H, Plon SE, Brinkley BR, chromatin is inhibited by Chk2 kinase in response to DNA damage. Cell Belmont JW. Cell cycle-dependent expression and nucleolar localiza- Cycle. 2016;15:3454–70. https​://doi.org/10.1080/15384​101.2016.12490​75. tion of hCAP-H. Mol Biol Cell. 2001;12:3527–37. https​://doi.org/10.1091/ 34. Ward JR, Vasu K, Deutschman E, Halawani D, Larson PA, Zhang D, Willard mbc.12.11.3527. B, Fox PL, Moran JV, Longworth MS. Condensin II and GAIT complexes 54. Zhang T, Paulson JR, Bakhrebah M, Kim JH, Nowell C, Kalitsis P, Hudson DF. cooperate to restrict LINE-1 retrotransposition in epithelial cells. PLoS Condensin I and II behaviour in interphase nuclei and cells undergoing Genet. 2017;13:e1007051. https​://doi.org/10.1371/journ​al.pgen.10070​51. premature chromosome condensation. Chromosome Res. 2016;24:243– 35. Huang K, Jia J, Wu C, Yao M, Li M, Jin J, Jiang C, Cai Y, Pei D, Pan G, Yao H. 69. https​://doi.org/10.1007/s1057​7-016-9519-7. Ribosomal RNA gene transcription mediated by the master genome 55 Xing X, Mroß C, Hao L, Munck M, Herzog A, Mohr C, Unnikannan CP, regulator protein CCCTC-binding factor (CTCF) is negatively regulated Kelkar P, Noegel AA, Eichinger L, Neumann S. Nesprin-2 interacts with by the condensin complex. J Biol Chem. 2013;288:26067–77. https​://doi. condensin component SMC2. Int J Cell Biol. 2017;2017:8607532. https​:// org/10.1074/jbc.M113.48617​5. doi.org/10.1155/2017/86075​32. 36. Yokoyama Y, Zhu H, Zhang R, Noma K. A novel role for the condensin II 56. Swygert SG, Kim S, Wu X, Fu T, Hsieh TH, Rando OJ, Eisenman RN, complex in cellular senescence. Cell Cycle. 2015;14:2160–70. https​://doi. Shendure J, McKnight JN, Tsukiyama T. Condensin-dependent chromatin org/10.1080/15384​101.2015.10497​78. compaction represses transcription globally during quiescence. Mol Cell. 37. Iwasaki O, Tanizawa H, Kim KD, Kossenkov A, Nacarelli T, Tashiro S, Majum- 2019;73:533–46.e4. https​://doi.org/10.1016/j.molce​l.2018.11.020. dar S, Showe LC, Zhang R, Noma KI. Involvement of condensin in cellular 57. Matson JP, House AM, Grant GD, Wu H, Perez J, Cook JG. Intrinsic check- senescence through gene regulation and compartmental reorganization. point defciency during cell cycle re-entry from quiescence. J Cell Biol. Nat Commun. 2019;10:5688. https​://doi.org/10.1038/s4146​7-019-13604​ 2019;218:2169–84. https​://doi.org/10.1083/jcb.20190​2143. -5. Wang et al. Cell Biosci (2020) 10:147 Page 7 of 7

58. Gosling KM, Makarof LE, Theodoratos A, Kim YH, Whittle B, Rui L, Wu H, 70. Rowley MJ, Lyu X, Rana V, Ando-Kuri M, Karns R, Bosco G, Corces VG. Con- Hong NA, Kennedy GC, Fritz JA, Yates AL, Goodnow CC, Fahrer AM. A densin II counteracts cohesin and RNA polymerase II in the establishment mutation in a chromosome condensin II subunit, kleisin beta, specifcally of 3D chromatin organization. Cell Rep. 2019;26(11):2890–903.e3. https​:// disrupts T cell development. Proc Natl Acad Sci U S A. 2007;104:12445–50. doi.org/10.1016/j.celre​p.2019.01.116. https​://doi.org/10.1073/pnas.07048​70104​. 71. Xu X, Yanagida M. Suppressor screening reveals common kleisin-hinge 59. Gosling KM, Goodnow CC, Verma NK, Fahrer AM. Defective T-cell interaction in condensin and cohesin, but diferent modes of regulation. function leading to reduced antibody production in a kleisin-beta Proc Natl Acad Sci USA. 2019;116:10889–98. https​://doi.org/10.1073/ mutant mouse. Immunology. 2008;125:208–17. https​://doi.org/10.111 pnas.19026​99116​. 1/j.1365-2567.2008.02831​.x. 72 Tapia-Alveal C, Lin SJ, O’Connell MJ. Functional interplay between 60 Rawlings JS, Gatzka M, Thomas PG, Ihle JN. Chromatin condensation via cohesin and Smc5/6 complexes. Chromosoma. 2014;123:437–45. https​:// the condensin II complex is required for peripheral T-cell quiescence. doi.org/10.1007/s0041​2-014-0474-9. EMBO J. 2011;30:263–76. https​://doi.org/10.1038/emboj​.2010.314. 73. Gallego-Paez LM. Tanaka H, Bando M. Takahashi M, Nozaki N. Nakato 61. Woodward J, Taylor GC, Soares DC, Boyle S, Sie D, Read D, Chathoth K, R, Shirahige K. Hirota T (2014) Smc5/6-mediated regulation of replica- Vukovic M, Tarrats N, Jamieson D, Campbell KJ, Blyth K, Acosta JC, et al. tion progression contributes to chromosome assembly during mitosis Condensin II mutation causes T-cell lymphoma through tissue-specifc in human cells. Mol Biol Cell 25:302 – 17. https​://doi.org/10.1091/mbc. genome instability. Genes Dev. 2016;30:2173–86. https​://doi.org/10.1101/ E13-01-0020. gad.28456​2.116. 74. Pryzhkova MV, Jordan PW. Conditional mutation of Smc5 in mouse 62. Swygert SG, Tsukiyama T. Unraveling quiescence-specifc repressive chro- embryonic stem cells perturbs condensin localization and mitotic pro- matin domains. Curr Genet. 2019;65:1145–51. https​://doi.org/10.1007/ gression. J Cell Sci. 2016;129:1619–34. https​://doi.org/10.1242/jcs.17903​6. s0029​4-019-00985​-9. 75. Swanson EC, Rapkin LM, Bazett-Jones DP, Lawrence JB. Unfold- 63. Wang HZ, Yang SH, Li GY, Cao X. Subunits of human condensins are ing the story of chromatin organization in senescent cells. Nucleus. potential therapeutic targets for cancers. Cell Div. 2018;13:2. https​://doi. 2015;6(4):254–60. https​://doi.org/10.1080/19491​034.2015.10576​70. org/10.1186/s1300​8-018-0035-3. 76. Graziano S, Gonzalo S. Mechanisms of oncogene-induced genomic 64. Hoare MW, Narita M. The power behind the throne: senescence and the instability. Biophys Chem. 2017;225:49–57. https​://doi.org/10.1016/j. hallmarks of cancer. Annu Rev Cancer Biol. 2018;2:175–94. https​://doi. bpc.2016.11.008. org/10.1146/annur​ev-cance​rbio-03061​7-05035​2. 77. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, 65. Chan ASL, Narita M. Short-term gain, long-term pain: the senescence life Lin Y, Zhou Z, Capell BC, Xu C, Xu M, et al. Cytoplasmic chromatin triggers cycle and cancer. Genes Dev. 2019;33:127–43. https​://doi.org/10.1101/ infammation in senescence and cancer. Nature. 2017;550:402–6. https​:// gad.32093​7.118. doi.org/10.1038/natur​e2405​0. 66. Wang J, Geesman GJ, Hostikka SL, Atallah M, Blackwell B, Lee E, Cook PJ, 79 van Ruiten MS, Rowland BD. SMC Complexes: universal DNA looping Pasaniuc B, Shariat G, Halperin E, Dobke M, Rosenfeld MG, Jordan IK, et al. machines with distinct regulators. Trends Genet. 2018;34:477–87. https​:// Inhibition of activated pericentromeric SINE/Alu repeat transcription doi.org/10.1016/j.tig.2018.03.003. in senescent human adult stem cells reinstates self-renewal. Cell Cycle. 79. Hassler M. Shaltiel IA, Haering CH. (2018) Towards a unifed model of 2011;10:3016–30. https​://doi.org/10.4161/cc.10.17.17543​. SMC complex function. Curr Biol 28:R1266-81. https​://doi.org/10.1016/j. 67. Potts PR, Yu H. The SMC5/6 complex maintains telomere length in ALT cub.2018.08.034. cancer cells through SUMOylation of telomere-binding proteins. Nat 80. Marko JF. De Los Rios P, Barducci A, Gruber S. (2019) DNA-segment-cap- Struct Mol Biol. 2007;14:581–90. https​://doi.org/10.1038/nsmb1​259. ture model for loop extrusion by structural maintenance of chromosome 68. Min J, Wright WE, Shay JW. Alternative lengthening of telomeres medi- (SMC) protein complexes. Nucleic Acids Res 47:6956–72. https​://doi. ated by mitotic DNA synthesis engages break-induced replication org/10.1093/nar/gkz49​7. processes. Mol Cell Biol. 2017;37:e00226-17. https​://doi.org/10.1128/ MCB.00226​-17. 69. Chavez A, George V, Agrawal V, Johnson FB. Sumoylation and the Publisher’s Note structural maintenance of chromosomes (Smc) 5/6 complex slow Springer Nature remains neutral with regard to jurisdictional claims in pub- senescence through recombination intermediate resolution. J Biol Chem. lished maps and institutional afliations. 2010;285:11922–30. https​://doi.org/10.1074/jbc.M109.04127​7.

Ready to submit your research ? Choose BMC and benefit from:

• fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions